Traditional concepts of the regulation of cellular energy regulation fail to explain a central feature of the pathophysiology of sepsis, increased non-oxidative glucose utilization and lactate production in the presence of sufficient oxygen to support oxidative metabolism, i.e., aerobic glycolysis. Preliminary results from this laboratory strongly suggest that lactate production by well-oxygenated skeletal muscles occurs under conditions which stimulate Na ion K ion transport across the plasma membrane. This linkage between aerobic glycolysis and activity of the Na ion, K ion - ATPase has been demonstrated previously in several tissues, but not in skeletal muscle. Moreover, much of the increased lactate production by muscles from septic animals appears to be linked to increased activity of the Na ion, K ion-ATPase. If glycolysis by skeletal muscle is not necessarily a symptom of hypoxia or impaired oxidative metabolism, then the clinical interpretation of high blood lactate in sepsis may be erroneous and therapies designed to increase oxygen delivery to tissues my be futile or irrelevant. If increased lactate production reflects not hypoxia but, rather, stimulation of Na ion, K ion - ATPase by increased intracellular Na ion, then new therapies must be directed toward correcting the underlying defect, namely, increased membrane permeability to Na ion. We will study the effects of monensin, sepsis and TNF on intracellular energy metabolites, glucose uptake, lactate and amino acid release, activity of the Na ion, K ion -ATPase, intracellular Na and K, and oxygen utilization in vitro. Studies of whole-body glucose metabolism in vivo will examine the effects in septic animals of reducing the activity of the Na ion, K ion -ATPase with ouabain. Other in vivo studies will explore linkage between TNF and changes in glycolysis through administration of TNF-neutralizing antiserum to septic animals. The research described here is aimed at extending the preliminary results and, ultimately, at identifying the causes of the underlying membrane defects. The results of these studies will permit the establishment of a firm link between two recognized phenomena in sepsis which were previously thought to be unrelated: (a) increased intracellular concentration of Na ion and (b) increased glycolysis and lactate production. Creating a solid experimental foundation for this connection is needed in order to devise appropriate therapies in the treatment of the metabolic abnormalities of sepsis.